Design and synthesis of unique morphinan-type molecules: Their application to the search for the unexplored binding domain between opioid receptors and morphinan ligands

Kenta Maeda; Tomoya Sugai; Akihisa Tokuda; Keita Kajino; Tsuyoshi Saitoh; Hiroshi Nagase; Noriki Kutsumura

doi:10.1016/j.bmcl.2024.129611

Design and synthesis of unique morphinan-type molecules: Their application to the search for the unexplored binding domain between opioid receptors and morphinan ligands

Bioorg Med Chem Lett. 2024 Feb 1:99:129611. doi: 10.1016/j.bmcl.2024.129611. Epub 2024 Jan 14.

Authors

Kenta Maeda¹, Tomoya Sugai², Akihisa Tokuda³, Keita Kajino¹, Tsuyoshi Saitoh⁴, Hiroshi Nagase⁵, Noriki Kutsumura⁶

Affiliations

¹ Degree Programs in Pure and Applied Sciences, Graduate School of Science and Technology, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan.
² International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
³ Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
⁴ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
⁵ Degree Programs in Pure and Applied Sciences, Graduate School of Science and Technology, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: [email protected].
⁶ Degree Programs in Pure and Applied Sciences, Graduate School of Science and Technology, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: [email protected].

PMID: 38228254
DOI: 10.1016/j.bmcl.2024.129611

Abstract

The morphinan skeleton is valued in drug discovery for its beneficial physicochemical properties and is recognized as a crucial template for opioid receptor ligands. In morphinan derivatives, it is well-established that the nitrogen atom within the piperidine ring (D-ring) interacts with the amino acid residues of the opioid receptors. This interaction is recognized as one of the crucial pharmacophores between the morphinan molecule and the opioid receptors. Consequently, the structure-activity relationships (SAR) surrounding the D-ring are not well-studied, due to concerns that structural transformations around the nitrogen at the 17-position could disrupt this interaction. In this study, we found that our novel morphinan-type ligands with a side chain containing a heteroatom positioned above the d-ring have binding affinity for the opioid receptors. These novel skeletons could provide unique templates with the desired side chain above the D-ring in the morphinan skeleton, and thus, potentially advance the SAR studies of morphinan ligands with the opioid receptors.

Keywords: Morphinan-type skeleton; Skeletal rearrangement; Structure–activity relationships.

MeSH terms

Ligands
Morphinans* / chemistry
Nitrogen
Receptors, Opioid* / metabolism
Receptors, Opioid, mu / metabolism
Structure-Activity Relationship

Substances

Receptors, Opioid
Morphinans
Receptors, Opioid, mu
Ligands
Nitrogen